Injection solutions containing pyridine carboxylic acid nu-hydroxymethylamides



United Sttes Patent INJECTION SOLUTIGNS gARBOXYLIC ACID N HYDROXYMETHYL MIDES Carl Richter, Schalfhausen, and Alfred Willi, Herblingen, Canton Schalfhausen, Switzerland, assignors to Cilag imited, Schaifhausen, Switzerland, a Swiss company No Drawing. Application September 21, 1955, Serial No. 535,735

Claims priority, application Switzerland September 24, 1954 2 Claims. (Cl. 167-65) This invention relates to injection solutions of N-hydroxymethyl pyridine carboxylic acid amides, substantially free of formaldehyde, containing a hexoseureide in a quantity not exceeding 15% by weight, and particularly to an injection solution of N-hydroxymethyl nicotinic acid amide substantially free of formaldehyde, containing a hexoseureide in a quantity not exceeding 15% by weight, but preferably in a quantity from 8% to 15% by weight.

In the past years, hydroxymethyl amides of pyridine carboxylic acids, and especially of nicotinic acid, have been introduced more and more in the medical practice. They are in particular used in the therapy of bile-duct troubles, in the chemotherapy of disbactery of the colon, and for similar purposes. The hydroxymethyl amides in question are usually applied perorally, however, in many cases also parenterally, and particularly intravenously.

Aqueous solutions of pyridine carboxylic acid hydroxymethyl amides, when stored for a long time, contain free formaldehyde, as an equilibrium takes place between pyridine carboxylic acid hydroxy methyl amides on one hand and pyridine carboxylic acid amides and formaldehyde on the other hand. Since, as is known, free formaldehyde, when applied intravenously, even in small concentrations, causes pain, there was a definite need for the production of aqueous solutions of pyridine carboxylic acid hydroxymethyl amides, which are free of or poor in formaldehyde.

An adjustment of the equilibrium status between pyridine carboxylic acid hydroxy methyl amide on one hand and pyridine carboxylic acid amide and formaldehyde on the other hand by addition of excessive pyridine carboxylic acid amide in favor of pyridine carboxylic acid hydroxy methyl amide was taken into consideration.

Further examinations of the situations showed that, in order to reduce the formaldehyde content to below 0.1%, pyridine carboxylic acid amide would have to be added in such quantities, that these would by far exceed the physiologically permissible measure. A solution to this problem could therefore not be found in this manner alone.

The value of the constant of the equilibrium [CH O]-[pyridine carboxylic acid amide] [pyridine carboxylic acid hydroxy methyl amide] within narrow limits,-fwh'ich had to be adapted to the physiological needs, so that also here'noabsolute success could be expected. With these alterations it was possible to reduce the velocity of decomposition to such an extent that for a few years the content of pyridine carboxylic acid hydroxy methyl amide does not sink substautially, but already a small decomposition grade is enough to let the content of formaldehyde reach the tolerance limit.

As a measure promising success in hindering the building of formaldehyde there could only be seen the addition of physiologically inert formaldehyde acceptors. However, known formaldehyde acceptors, such as urea, thiourea, aminotriazines, etc. are disadvantageous insofar as in the presence of formaldehyde they polymerize easily and form products which are not soluble in water.

It was now surprisingly found that ureides of hydroxyaldehydes, ureides of polyhydroxyaldehydes, or ureides of polyhydroxyketones, when added to aqueous solutions of hydroxy methyl pyridine carboxylic acid amides are capable to reduce the formaldehyde content of such solvents to below 1%. Ureides of hexoses and in particular the glucose ureide have proved especially effective.

The following contents of free formaldehyde in 4% aqueous solutions of nicotinic acid hydroxy methyl amide with 0.01 M citrate buffer (pl-1:60) at room temperature (18 to 25 C.) were established:

(G=glucosc ureide.)

From the values of the above table can be interpolated that an addition of 8% by weight glucose ureide suflices to reduce the formaldehyde content, even after a longer storage, to below 0.1%, and extrapolated that additions of over 15% by weight glucose ureide do not yield a further substantial reduction of the formaldehyde content. This fact was confirmed by extended experiments with various additions of glucose ureide.

It has been proved that the mechanism of the formaldehyde bond consists in a hfliydroxy methylation of the ureide. The quantitative conformance of the CHzO- values in the above table with the calculated values has shown that glucose ureide reacts with formaldehyde only when the latter is already split oif from the hydroxy methyl nicotinic acid amide.

The formaldehyde accepting addition, the glucose ureide, and the hydroxy methyl glucose ureide which forms with the time, are exceptionally well soluble in water, so that the aqueous solutions never become turbid. They also show an extremely low toxicity, so that the two bodies, when used in normal dosing limits, may be considered physiologically indifferent. White mice bear for instance more than 20 g./kg. glucose ureide when applied perorally or subcutaneously, and more than 10 g./ kg. when applied intravenously.

In the same manner as described above, there may also be obtained with the aid of hexose ureides solutions of isonicotinic acid-N-hydroxymethyl amide which are practically free of formaldehyde.

What we claim is:

1. An injection solution of N-hydroxy methyl nicotinic acid amide substantially free of formaldehyde, contaim'ng glucose ureide in a quantity from 8% to 15% by References Cited in the file of this patent weight FOREIGN PATENT 2. Injection solutions of N-hydroxy methyl pyridine 809 316 F S carboxylic acid amides substantially free of formalde- 1936 hyde, containiug glucose ureide in a quantity from 8% 5 OTHER REFERENCES to 15% by weight Gehes Codex, 8th ed., p. 103, Wissenschaftlische Verlagsgesellschaft, Stuttgart. 

1. AN INJECTION SOLUTIN OF N-HYDROXY METHYL NICOTINIC ACID AMIDE SUBSTANTIALLY FREE OF FORMALDEHYDE, CONTAINING GLUCOSE UREIDE IN A QUANTITY FROM 8% TO 15% BY WEIGHT. 